Based on our recent findings in sleeping humans and dogs we propose that the ventilatory responsiveness to CO2 below eupnea is highly labile depending on the type and direction of prevailing ventilatory drive and is a critical determinant of many types of breathing instability and apnea. We propose five major aims to study causes and consequences of a labile apneic threshold on the CO2 reserve (i.e., PETCO2 EUPNEA -- PETCO2APNEA ; an index of propensity for ventilatory instability). First, we will use the sleeping dog model and our pressure support ventilation (PSV) method to determine the CO2 reserve and change in the susceptibility to apnea caused by raised left atrial pressure, as occurs in congestive heart failure. Aims 2 & 3 will utilize our intact sleeping dog preparation in which the carotid chemoreceptor is isolated and perfused via extracorporeal circulation. We will determine the sensitivities of the central vs. peripheral chemoreceptors to transient reductions in PaCO2 and their relative contributions to the genesis of apnea. Our capability for isolating central from peripheral chemoreceptors in the intact sleeping animal will also be used to determine the relative importance of peripheral chemoreceptor hypoxia vs. CNS hypoxia in determining CO2 reserve and the propensity for ventilatory instability. In Aim 4, we will use sleeping humans to study the causes and consequences to ventilatory stability of the dynamic changes in cerebral blood flow which accompany periodic breathing during sleep in hypoxia. Finally, we will test the hypothesis that obstructive sleep apnea patients have a propensity for unstable respiratory motor output and a sensitive apneic threshold (i.e., narrowed CO2 reserve) because of their chronic exposure to nocturnal hypoxemia. We will test this hypothesis further by exposing dogs to chronic intermittent hypoxia to determine if their propensity for ventilatory instability increases over the duration of chronic intermittent hypoxic exposure.